FK506 is a potent immunosuppressant and, like cyclosporin A [Borel, J. G. et al., Agents and Actions, 6, 468-471 (1976)], it is often used for preventing allograft rejection [Thomson, A. W., Immunol. Today, 10, 6-9 (1989)]. It is considered that the mechanism of its immunosuppresant action is in focus on the suppression of translation, during T cell activation [Tocci, M. et al., J. Immunol., 143, 718-726 (1989)], of a series of lymphokine genes which is critical to early immune responses. However, the precise mechanism remains unclear.
Recently, an AF506 binding protein was found in human T cells. It was identified as the 12 kDa cytosolic receptor of FK506 and shown to have peptidylprolyl cistrans isomerase activity (PPIase activity) [Siekier, J. et al., J. Immunol., 143, 1580-1583 (1989)].
Subsequently, on the basis of its amino acid sequence, a number of FK506 binding proteins (FKBPs) and corresponding cDNA clones have been isolated and the nucleotide sequences of said clones have been determined [for example, human FKBPs such as FKBP-12 (Standaert, R. F. et al., Nature, 346, 671-674 (1990); Maki, N, et al., Proc. Natl. Acad. Sci. USA, 87, 5440-5443 (1990)), FKBP-13 (Jin, Y. et al., Proc. Natl. Acad. Sci. USA, 88, 6677-6681 (1991)), FKBP-25 (Wiederrecht, G. et al., Biochem. Biophys. Res. Comm., 185, 298-303 (1992)) and FKBP-52 (Peattie, D. A. et al., Proc. Natl. Acad. Sci. USA, 89, 10974-10978 (1992)) as well as murine FKBP (Nelson, P. A. et al., Gene, 109, 255-258 (1991)), bovine FKBP (Mozier, N. M. et al., Eur. J. Biochem., 194, 19-23 (1990)), yeast FKBP (Heitman, J. et al., Proc. Natl. Acad. Sci. USA, 88, 1948-1952 (1991)), Neurospora crassa FKBP (Tropschug, M. et al., Nature, 346, 674-677 (1990)), Neisseria meningitis FKBP (Sampson, B. A. et al., Proc. Natl. Acad. Sci. USA, 89, 1164-1168 (1992)), etc.].
The above-mentioned FKBPs all have PPIase activity, which is presumably essential for protein folding during protein synthesis in cells [Ficher, G. et al., Biomed. Biochim. Acta, 43, 1101-1111 (1984)]. Although no clear evidence is available to prove that said PPIase activity is necessary for T cell activation, binding of FK506 to FKBPs is believed to bring about inhibition of PPIase activity and thereby inactivate T cells [Tropschug, M. et al., Nature, 346, 674-677 (1990)].